5-chloro-2-(methylsulfonyl)benzoic acid | 720689-28-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 5-chloro-2-(methylsulfonyl)benzoic acid
• 英文别名: 5-chloro-2-methylsulfonylbenzoic acid
• CAS: 720689-28-1
• 化学式: C₈H₇ClO₄S
• 分子量: 234.66
• InChiKey: SPTLHSBGLBPOOY-UHFFFAOYSA-N

物化性质

• 熔点：
  155-160 °C(Solv: benzene (71-43-2))
• 沸点：
  449.9±45.0 °C(Predicted)
• 密度：
  1.507±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  14
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  79.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5-chloro-2-(methylsulfonyl)benzoic acid 在 ammonium hydroxide 、 氯化亚砜 、 硫酸 、 硝酸 、 N,N-二甲基甲酰胺 作用下， 以 丙酮 为溶剂， 反应 2.0h， 生成 5-chloro-2-(methylsulfonyl)-4-nitrobenzamide
  参考文献：
  名称：

  Aziridinyldinitrobenzamides:  Synthesis and Structure−Activity Relationships for Activation by E. coli Nitroreductase

  摘要：

  The 5-aziridinyl-2,4-dinitrobenzamide CB 1954 is a substrate for the oxygen-insensitive nitroreductase (NTR) from E. coli and is in clinical trial in combination with NTR-armed adenoviral vectors in a GDEPT protocol; CB 1954 is also of interest for selective deletion of NTR-marked cells in normal tissues. Since little further drug development has been carried out around this lead, we report here the synthesis of more soluble variants and regioisomers and structure-activity relationship (SAR) studies. The compounds were primarily prepared from the corresponding chloro(di)nitroacids through amide side chain elaboration and subsequent aziridine formation. One-electron reduction potentials [E(1)], determined by pulse radiolysis, were around -400 mV, varying little for aziridinyldinitrobenzamide regioisomers. Cytotoxicity in a panel of NTR-transfected cell lines showed that in the CB 1954 series there was considerable tolerance of substituted CONHR side chains. The isomeric 2-aziridinyl-3,5-dinitrobenzamide was also selective toward NTR+ve lines but was approximately 10-fold less potent than CB 1954. Other regioisomers were too insoluble to evaluate. While CB 1954 gave both 2- and 4-hydroxylamine metabolites in NTR+ve cells, related analogues with substituted carboxamides gave only a single hydroxylamine metabolite possibly because the steric bulk in the side chain constrains binding within the active site. CB 1954 is also a substrate for the two-electron reductase DT-diaphorase, but all of the other aziridines (regioisomers and close analogues) were poorer substrates with resulting improved specificity for NTR. Bystander effects were determined in multicellular layer cocultures and showed that the more hydrophilic side chains resulted in a modest reduction in bystander killing efficiency. A limited number of analogues were tested for in vivo activity, using a single ip dose to CD-1 nude mice bearing WiDr-NTRneo tumors. The most active of the CB 1954 analogues was a diol derivative, which showed a substantial median tumor growth delay (59 days compared with >85 days for CB 1954) in WiDr xenografts comprising 50% NTR+ve cells. The diol is much more soluble and can be formulated in saline for administration. The results suggest there may be advantages with carefully selected analogues of CB 1954; the weaker bystander effect of its diol derivative may be an advantage in the selective cell ablation of NTR-tagged cells in normal tissues.

  DOI：

  10.1021/jm0498699
• 作为产物：
  描述：

  5-氯-2-氟苯甲酸甲酯 在 水 、 间氯过氧苯甲酸 、 sodium hydroxide 作用下， 以 四氢呋喃 、 N,N-二甲基乙酰胺 、 乙酸乙酯 为溶剂， 反应 19.0h， 生成 5-chloro-2-(methylsulfonyl)benzoic acid
  参考文献：
  名称：

  选择性α1D肾上腺素受体拮抗剂TAK-259的代谢产物的结构测定，合成和生物学评估

  摘要：

  5-氯-1-（5-氯-2-（甲基磺酰基）苄基）-2-亚氨基-1,2-二氢吡啶-3-羧酰胺盐酸盐（TAK-259）是一种新颖的，选择性的，口服活性的α1D肾上腺素受体拮抗剂具有抗尿频作用。从猴子尿液样本中鉴定出TAK-259的代谢物（2）。为了阐明2的结构，进行了TAK-259处理的猴尿中代谢物的提取和纯化。使用NMR对纯化的化合物进行结构分析表明，该化合物为2-氨基-5-氯-1- [5-氯-2-（甲基磺酰基）苄基] -4-氧代-1,4-二氢吡啶-3-羧酰胺（2a）。化合物2a的真实样品通过4-甲氧基吡啶-2-胺的区域选择性烷基化反应合成了α-氨基丁酸酯。代谢物的生物活性的图2a还评价，并且化合物发现不具有朝向任何已知的α亲和力1种肾上腺素受体亚型。

  DOI：

  10.1016/j.tet.2016.08.013

文献信息

• US5656573A
  申请人：——

  公开号：US5656573A

  公开（公告）日：1997-08-12
• US5650533A
  申请人：——

  公开号：US5650533A

  公开（公告）日：1997-07-22
• US5747424A
  申请人：——

  公开号：US5747424A

  公开（公告）日：1998-05-05
• US5859283A
  申请人：——

  公开号：US5859283A

  公开（公告）日：1999-01-12
• Aziridinyldinitrobenzamides:  Synthesis and Structure−Activity Relationships for Activation by <i>E. </i><i>coli</i> Nitroreductase
  作者：Nuala A. Helsby、Graham J. Atwell、Shangjin Yang、Brian D. Palmer、Robert F. Anderson、Susan M. Pullen、Dianne M. Ferry、Alison Hogg、William R. Wilson、William A. Denny

  DOI：10.1021/jm0498699

  日期：2004.6.1

  The 5-aziridinyl-2,4-dinitrobenzamide CB 1954 is a substrate for the oxygen-insensitive nitroreductase (NTR) from E. coli and is in clinical trial in combination with NTR-armed adenoviral vectors in a GDEPT protocol; CB 1954 is also of interest for selective deletion of NTR-marked cells in normal tissues. Since little further drug development has been carried out around this lead, we report here the synthesis of more soluble variants and regioisomers and structure-activity relationship (SAR) studies. The compounds were primarily prepared from the corresponding chloro(di)nitroacids through amide side chain elaboration and subsequent aziridine formation. One-electron reduction potentials [E(1)], determined by pulse radiolysis, were around -400 mV, varying little for aziridinyldinitrobenzamide regioisomers. Cytotoxicity in a panel of NTR-transfected cell lines showed that in the CB 1954 series there was considerable tolerance of substituted CONHR side chains. The isomeric 2-aziridinyl-3,5-dinitrobenzamide was also selective toward NTR+ve lines but was approximately 10-fold less potent than CB 1954. Other regioisomers were too insoluble to evaluate. While CB 1954 gave both 2- and 4-hydroxylamine metabolites in NTR+ve cells, related analogues with substituted carboxamides gave only a single hydroxylamine metabolite possibly because the steric bulk in the side chain constrains binding within the active site. CB 1954 is also a substrate for the two-electron reductase DT-diaphorase, but all of the other aziridines (regioisomers and close analogues) were poorer substrates with resulting improved specificity for NTR. Bystander effects were determined in multicellular layer cocultures and showed that the more hydrophilic side chains resulted in a modest reduction in bystander killing efficiency. A limited number of analogues were tested for in vivo activity, using a single ip dose to CD-1 nude mice bearing WiDr-NTRneo tumors. The most active of the CB 1954 analogues was a diol derivative, which showed a substantial median tumor growth delay (59 days compared with >85 days for CB 1954) in WiDr xenografts comprising 50% NTR+ve cells. The diol is much more soluble and can be formulated in saline for administration. The results suggest there may be advantages with carefully selected analogues of CB 1954; the weaker bystander effect of its diol derivative may be an advantage in the selective cell ablation of NTR-tagged cells in normal tissues.